Heterozygous Insulin Receptor (INSR) Mutation Associated with Neonatal Hyperinsulinemic Hypoglycaemia and Familial Diabetes Mellitus: Case Series

Mutations in the insulin receptor (INSR) gene are associated with insulin resistance and hyperglycaemia. Various autosomal dominant heterozygous INSR mutations leading to hyperinsulinemic hypoglycaemia (HH) have been described in adults and children (more than 3 years of age) but not in the neonatal period. Family 1: A small for gestational age (SGA) child born to a mother with gestational diabetes presented with persistent hypoglycaemia, was diagnosed with HH and responded well to diazoxide treatment. Diazoxide was gradually weaned and discontinued by 8 months of age. Later, the younger sibling had a similar course of illness. On genetic analysis a heterozygous INSR missense variant p.(Met1180Lys) was found in the siblings, mother and grandfather but not in the father. Family 2: A twin preterm and SGA baby presented with persistent hypoglycaemia, which was confirmed as HH. He responded to diazoxide, which was subsequently discontinued by 10 weeks of life. Genetic analysis revealed a novel heterozygous INSR missense variant p.(Arg1119Gln) in the affected twin and the mother. Family 3: An SGA child presented with diazoxide responsive HH. Diazoxide was gradually weaned and discontinued by 9 weeks of age. Genetic analysis revealed a novel heterozygous INSR p.(Arg1191Gln) variant in the proband and her father. We report, for the first time, an association of INSR mutation with neonatal HH responsive to diazoxide therapy that resolved subsequently. Our case series emphasizes the need for genetic analysis and long-term follow up of these patients.

Maternal attitude towards delaying puberty in girls with and without a disability: a questionnaire-based study from the United Arab Emirates.

BACKGROUND: Parental anxiety about the impact of puberty/menses, particularly in girls with severe disability leads to seeking therapeutic pubertal suppression. We aim to explore maternal attitudes and reasons for seeking pubertal suppression. METHODS: Mothers of girls receiving gonadotropin -releasing hormone analogue therapy in Mafraq hospital, Abu Dhabi were enrolled in the study. A semistructured interview was conducted to ascertain possible reasons for delaying puberty. The study group was divided into girls with a disability with central precocious puberty (CPP) or normal puberty and girls without a disability presenting with CPP. RESULTS: 42 mother-daughter pairs were enrolled and divided into two groups; group A: 15 girls with CPP with no disability; group B: 27 girls with disability (10 had CPP (group B1) and 17 had normal pubertal timing (group B2)). Mothers in group A aimed to delay puberty, while in group B, 13 (48%) mothers desired to halt puberty and 7 (26%) requested permanent surgical intervention. Fear of short stature (15, 100%), inability to cope psychologically (10, 67%) and fear of peer rejection (9, 60%) were the main concerns in group A. In group B, mothers were concerned about menstrual hygiene management (25, 92.5%), fear of child abuse or unwanted pregnancy (15, 55%) and fear of inability to express pain/discomfort with menstruation (8, 30%). CONCLUSION: Mothers of girls with a disability commonly seek medical help to delay/halt puberty due to concerns about menstrual hygiene. Short final height was the main concern for girls without a disability. Culture and religion play an important role in puberty management in girls with a disability.

Retrospective review of Synacthen testing in infants.

BACKGROUND: A subnormal cortisol response (30 min level (C30min)<550 nmol/L) to synthetic adrenocorticotrophic hormone/Synacthen test (SDST) in all infants does not necessarily indicate underlying or persistent hypothalamic-pituitary-adrenal axis pathology. METHODS: We retrospectively evaluated the diagnoses and outcomes in 68 infants who had a SDST at age <6 months from 2011 to 2014. RESULTS: 29 (43%) infants had a subnormal SDST. Causative pathology was identified in 9/29 (31%). In 20/29 (69%) with no identified pathology, repeat SDST was normal in 18/20 (90%) at median age 0.6 (range 0.1-3.2) years but persistently subnormal in 2. Those with a transient abnormality were more likely to be small for gestational age (P=0.03) and had higher initial SDST C30min (390 nmol/L vs 181 nmol/L, P=0.01) than those with pathology. CONCLUSION: Specific aetiology can be identified in a third of infants with a subnormal SDST. When the aetiology remains elusive, adrenal function should be reassessed as the problem can be transient.

The neuroendocrine sequelae of paediatric craniopharyngioma: a 40-year meta-data analysis of 185 cases from three UK centres.

OBJECTIVES: The management of paediatric craniopharyngiomas was traditionally complete resection (CR), with better reported tumour control compared to that by partial resection (PR) or limited surgery (LS). The subsequent shift towards hypothalamic sparing, conservative surgery with adjuvant radiotherapy (RT) to any residual tumour aimed at reducing neuroendocrine morbidity, has not been systematically studied. Hence, we reviewed the sequelae of differing management strategies in paediatric craniopharyngioma across three UK tertiary centres over four decades. METHODS: Meta-data was retrospectively reviewed over two periods before (1973-2000 (Group A: n = 100)) and after (1998-2011 (Group B: n = 85)) the introduction of the conservative strategy at each centre. RESULTS: Patients had CR (A: 34% and B: 19%), PR (A: 48% and B: 46%) or LS (A: 16% and B: 34%), with trends reflecting the change in surgical approach over time. Overall recurrence rates between the two periods did not change (A: 38% vs B: 32%). More patients received RT in B than A, but recurrence rates were similar: for A, 28% patients received RT with 9 recurrences (32%); for B, 62% received RT with 14 recurrences (26%). However, rates of diabetes insipidus (P = 0.04), gonadotrophin deficiency (P < 0.001) and panhypopituitarism (P = 0.001) were lower in B than those in A. In contrast, post-operative obesity (BMI SDS >+2.0) (P = 0.4) and hypothalamic (P = 0.1) and visual (P = 0.3) morbidity rates were unchanged. CONCLUSION: The shift towards more conservative surgery has reduced the prevalence of hormone deficiencies, including diabetes insipidus, which can be life threatening. However, it has not been associated with reduced hypothalamic and visual morbidities, which remain a significant challenge. More effective targeted therapies are necessary to improve outcomes.

Acceptance of a reusable self-injection device for recombinant human growth hormone: final data from a questionnaire-based, cross-sectional, international, multicenter, observational study in pediatric patients.

BACKGROUND: A questionnaire-based survey was conducted to assess attitudes toward a reusable self-injection system (SurePal™) among pediatric patients with growth disturbances who were prescribed treatment with Omnitrope(®) within routine clinical practice. METHODS: This was a multicenter, observational study, incorporated into the noninterventional PAtients TReated with Omnitrope(®) (PATRO) Children study. Included subjects, or their caregivers, completed a questionnaire on the following five main areas: attractiveness of SurePal™, training received, using the device, the low drug wastage system, and experience versus other devices used previously (pretreated patients). Responses were based on a 5-point scale, with 2 being the best possible outcome and -2 the worst possible outcome. RESULTS: In total, 550 patients were included in this study (338 from France, 169 from Germany, and 43 from the UK). The mean age ± standard deviation of participants was 10.8±3.5 years; the majority (57%) were male and growth hormone treatment naïve (88%). Almost half (49.8%) of children prepared their SurePal™ for injection themselves and 45.5% performed injections themselves. As patients progressed into their teens, the majority (≥75%) favored preparing SurePal™ and performing injections themselves, rather than seeking assistance. The attractiveness of SurePal™ was rated as excellent/good by 84.7% of patients overall; this rating was similarly high (≥79%) across countries and age-groups. Preparing (88.8%) and using (83.3%) SurePal™ were rated as very easy/easy by most patients; these ratings were similarly high, irrespective of country or age-group. The dose-memory function was rated as very helpful/helpful by 66.2% of patients. Among 246 patients who reported using the low drug-waste feature, 87.4% found it helpful. Among pretreated patients (n=64), 78.2% reported that SurePal™ was much better/better than their previous device. CONCLUSION: These data confirm the ease of use and patient preference for SurePal™ among pediatric patients with growth disturbances.

Feeding Problems Are Persistent in Children with Severe Congenital Hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is a rare but severe disorder of hypoglycemia in children, often complicated by brain injury. In CHI, the long-term prevention of hypoglycemia is dependent on reliable enteral intake of glucose. However, feeding problems (FPs) often impede oral glucose delivery, thereby complicating the management of hypoglycemia. FPs have not been systematically characterized in follow-up in a cohort with CHI. AIMS: We aimed to determine the prevalence, types, and persistence of FPs in a cohort of children with CHI and investigate potential causal factors. METHODS: FPs were defined as difficulty with sucking, swallowing, vomiting, and food refusal (or a combination) in an observational study in 83 children in a specialized CHI treatment center. The prevalence of FPs at diagnosis, 6, and 12 months after diagnosis were noted. Genetic mutation status and markers of severity of CHI were tested for association with FPs. RESULTS: A third of children with CHI had FPs (n = 28), of whom 93% required antireflux medication and 75% required nasogastric and gastrostomy tube feeding. Sucking and swallowing problems were present at diagnosis but absent later. Vomiting was present in 54% at 6 months, while food refusal was present in 68% at 6 months and 52% at 12 months. The age at commencing and stopping nasogastric tube feeding did not correlate with FPs frequency at 6 and 12 months. Children with FPs had severe hypoglycemia at diagnosis and required glucagon infusion more often [odds ratio (OR) (95% confidence intervals) (95% CI) 28.13 (2.6-300.1), p = 0.006] to normalize glucose levels. FPs were more frequent in those with diffuse CHI undergoing subtotal pancreatectomy [n (%) = 10 (35%) vs. 0 (0%), p < 0.001], in contrast to those with spontaneous resolution [6 (22%) vs. 32 (58%), p = 0.002]. Those undergoing focal lesionectomy also had reduced FPs at 6 months after diagnosis [OR (95% CI) 0.01 (0.0-0.2), R (2) = 0.42, p = 0.004]. These observations suggest that persistence of hyperinsulinism was associated with FPs. CONCLUSION: FPs occur in a significant proportion of children with CHI. Severe hyperinsulinism, rather than nasogastric tube feeding or medications, is the main factor associated with FPs.

Acceptability of the reusable SurePal™ self-injection device for Omnitrope(®) among pediatric patients: results from a questionnaire-based, cross-sectional, multicenter observational study.

BACKGROUND: SurePal™ is a reusable self-injection system that has been developed to support daily administration of Omnitrope(®) (Sandoz, Kundl, Austria). A questionnaire-based cross-sectional survey was conducted to evaluate acceptability of, and preference for, SurePal™ in pediatric patients who were prescribed treatment with Omnitrope(®) within routine clinical care. METHODS: This multicenter, observational study was incorporated into the ongoing non-interventional PATRO (PAtients TReated with Omnitrope(®)) Children study. Patients (or caregivers) were provided with a questionnaire that included five main topics; attractiveness of the device, training received, using SurePal™, the low drug wastage system, and experience versus other devices used previously (where applicable). Questions were scored on a 5-point scale, with -2 being the worst possible outcome (eg, very hard/very poor) and 2 being the best possible outcome (eg, very easy/excellent). RESULTS: A total of 186 patients were included in this study (Germany, n=154; UK, n=32). The attractiveness of SurePal™ was rated as excellent/good by 87.1% of patients. Overall, 86.5% of patients found that using their SurePal™ was very easy/easy. Almost all patients (96.2%) found that preparing their SurePal™ for injection was very easy/easy, and 89.2% found that injecting with SurePal™ was very easy/easy. 85.5% of patients recorded that the dose memory function was helpful, and 87.6% that taking their SurePal™ apart after an injection was very easy/easy. Of the 88 patients who recorded that they had used the low drug waste feature, 89.8% found the feature to be helpful. Among pre-treated patients (n=42), 81% recorded that SurePal™ was much better/better than their previously used device. CONCLUSION: This questionnaire-based cross-sectional survey in pediatric patients confirms the ease of use and patient preference for SurePal™, a reusable self-injection system that has been developed to support daily administration of Omnitrope(®).

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

Reduced Glycemic Variability in Diazoxide-Responsive Children with Congenital Hyperinsulinism Using Supplemental Omega-3-Polyunsaturated Fatty Acids; A Pilot Trial with MaxEPA(R.).

OBJECTIVE: Congenital hyperinsulinism (CHI) is a rare condition of hypoglycemia where therapeutic options are limited and often complicated by side-effects. Omega-3-polyunsaturated fatty acids (PUFA), which can suppress cardiac myocyte electrical activity, may also reduce ion channel activity in insulin-secreting cells. PUFA supplements in combination with standard medical treatment may improve glucose profile and may reduce glycemic variability in diazoxide-responsive CHI. DESIGN: Open label pilot trial with MaxEPA(R) liquid (eicosapentaenoic and docosahexaenoic acid) PUFA (3 ml/day for 21 days) in diazoxide-responsive CHI patients (https://eudract.ema.europa.eu/, EudraCT number 201100363333). METHODS: Glucose levels were monitored pre-treatment, end of treatment, and at follow-up by subcutaneous continuous glucose monitoring systems (CGMS) in 13 patients (7 girls) who received PUFA. Outcome measures were an improved glucose profile, reduced glycemic variability quantified by a reduction in the frequency of glucose levels <4 and >10 mmol/l, and safety of PUFA. All children were analyzed either as intention to treat (n = 13) or as per protocol (n = 7). RESULTS: Mean (%) CGMS glucose levels increased by 0.1 mmol/l (2%) in intention to treat and by 0.4 mmol/l (8%) in per protocol analysis (n = 7). The frequency of CGMS <4 mmol/l was significantly less at the end of treatment than in the pre-treatment period [556 (7%) vs. 749 (10%)]. Similarly, the frequency of CGMS >10 mmol/l, was also less at the end of treatment [27 (0.3%) vs. 49 (0.7%)]. Except for one child with increased LDL cholesterol, all safety parameters were normal. CONCLUSION: MaxEPA(R) was safe and reduced glycemic variability, but did not increase glucose profiles significantly in diazoxide-responsive CHI. The supplemental value of PUFA should be evaluated in a comprehensive clinical trial.

Abnormal Neurodevelopmental Outcomes are Common in Children with Transient Congenital Hyperinsulinism.

INTRODUCTION: Neuroglycopenia is recognized to be associated with abnormal neurodevelopmental outcomes in 26-44% of children with persistent congenital hyperinsulinism (P-CHI). The prevalence of abnormal neurodevelopment in transient CHI (T-CHI) is not known. We have aimed to investigate abnormal neurodevelopment and associated factors in T-CHI and P-CHI. MATERIALS AND METHODS: A cohort of children with CHI (n = 67, age 2.5-5 years) was assessed at follow-up review and noted to have normal or abnormal (mild or severe) neurodevelopmental outcomes for the domains of speech and language, motor, and vision. Children were classified as P-CHI (n = 33), if they had undergone surgery or remained on medical therapy, or T-CHI (n = 34), if medical treatment for hypoglycemia was stopped. RESULTS: Overall, abnormal neurodevelopment was present in 26 (39%) children with CHI, of whom 18 (69%) were severe. Importantly, the incidence of abnormal neurodevelopment in T-CHI was similar to that in P-CHI (30 vs. 47% respectively, p = 0.16). The prevalence of severe abnormal neurodevelopment in speech, motor, and vision domains was similar in both T-CHI and P-CHI children. For this cohort, we found that the severity of disease [based upon maximal diazoxide dose (odds ratio 95% confidence intervals) 1.3 (1.1; 1.5), p = 0.03], and early presentation of CHI <7 days following birth [5.9 (1.3; 27.8), p = 0.02] were significantly associated with abnormal neurodevelopment. There was no significant association with gender, genotype, or the histopathological basis of CHI. CONCLUSION: Abnormal neurodevelopment was evident in one third of children with both T-CHI and P-CHI, early presentation and severe CHI being risk factors. Early recognition and rapid correction of hypoglycemia are advocated to avoid abnormal neurodevelopment in children with CHI.

The association of cardiac ventricular hypertrophy with congenital hyperinsulinism.

OBJECTIVE: Ventricular hypertrophy (VH) has been observed in children with congenital hyperinsulinism (CHI), a condition of hypoglycaemia characterised by dysregulated insulin secretion, but the prevalence is not known. PATIENTS AND METHODS: Cardiac assessment was performed in children (n=49) with CHI at diagnosis and follow-up. Two dimensional and Doppler echocardiography studies were used to assess cardiac structures, while M-mode study was used to measure left ventricular (LV) dimensions, subsequently converted to Z scores. Where possible, LV hypertrophy was confirmed by LV mass index (g/m(2.7)) >95th centile. RESULTS: Cardiac structural lesions were found in 14 (28%) children. At initial echocardiography, VH was present in 31 (65%) children with median (range) LV posterior wall dimension in diastole Z scores of +1.6 (-2.4 to +5.8) and interventricular septal wall dimension in end diastole Z scores of +1.9 (-1.7 to +17.2). At follow-up echocardiography, performed after an interval of 178 (45-390) days, VH persisted in 16 (33%) children. In regression analysis, the presence of VH (odds ratio (95% confidence intervals) 1.1 (1.0-1.2), P=0.04) at initial echocardiography was correlated with maximum glucose requirement at diagnosis, indicating that severity of CHI at presentation may play a role in the pathogenesis of VH. CONCLUSIONS: A significant proportion of children with CHI have cardiac structural lesions. A majority also have VH, which may be associated with the severity of CHI at diagnosis. VH may persist in some children, which requires careful long-term cardiac review.

Persistent Müllerian duct syndrome: lessons learned from managing a series of eight patients over a 10-year period and review of literature regarding malignant risk from the Müllerian remnants.

UNLABELLED: Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Approximately 200 cases of persistent Müllerian duct syndrome have been reported over the last 50 years and most authors suggest leaving the Müllerian remnant in situ because of the difficulty in dissection and the presumed absence of risk of malignancy. However, with increasing reports of Müllerian malignancies emerging, we report our 10-year experience of managing patients with persistent Müllerian duct syndrome, with removal of müllerian remnants. This case series shows that there is an increased risk of Müllerian malignancy that was previously unknown. With the laparoscopic approach, orchidopexy with simultaneous removal of Müllerian remnants could be accomplished with minimal surgical trauma and the benefit of no malignancy risk in the future. This is a new technique that has not been previously performed. Considering the current evidence of malignancy in the Müllerian remnant, surgeons would need to discuss with families about removal of remnants or long-term monitoring. OBJECTIVES: • To describe the presentation and management of eight patients with persistent Müllerian duct syndrome (PMDS) seen over a 10-year period at our tertiary centre. • To review the literature of Müllerian malignancies reported in PMDS. PATIENTS AND METHODS: • The hospital records of eight patients with PMDS were retrospectively reviewed between 2001 and 2011. • Extensive PubMed searches for PMDS and Müllerian malignancy were performed. RESULTS: • Eleven cases with PMDS and malignancy of the Müllerian remnants were identified. • From our own PMDS series: five males presented with bilateral undescended testes and three had unilateral undescended testis. • We found that the Müllerian remnants could be removed by laparoscopy and three patients had simultaneous laparoscopic removal of the Müllerian structures and laparoscopic orchidopexy. CONCLUSIONS: • The principle aim of orchidopexy with simultaneous laparoscopic removal of the Müllerian structures can be accomplished with minimal surgical trauma and the benefit of no malignancy risk in the future. • Surgeons should consider excision of the Müllerian remnants where possible.

An observational study of type 2 diabetes within a large Australian tertiary hospital pediatric diabetes service.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is emerging as a significant clinical problem within the pediatric population. OBJECTIVE: The objective of this study was to identify patients with T2DM in a large tertiary hospital diabetes service and examine aspects relating to clinical course and management. METHODS: An initial audit of our diabetes service (over 6 yr) was followed by a 2-yr period of prospective case ascertainment to identify patients with T2DM. Comprehensive data collection was then undertaken in these individuals. RESULTS: Within our service (n = 1574), 33 young people with T2DM were identified. Significant levels of co-morbidity were evident - dyslipidaemia (56%), microalbuminuria (45%), hypertension (30%) and abnormal retinal findings (25%). Hypertension was more likely in those with greater initial and follow-up body mass index (BMI) [mean (SD) BMI: 36.3 (5.0) vs. 28.0 (6.3) kg/m(2) , p = 0.001, and 36.8 (5.3) vs. 28.5 (7.8) kg/m(2) , p = 0.007, respectively] and BMI standard deviation score (SDS) [mean (SD) BMI SDS: 2.34 (0.30) vs. 1.72 (0.66), p = 0.001, and 2.26 (0.31) vs. 1.38 (0.87), p < 0.001, respectively], whereas abnormal retinal findings were seen in those with higher HbA1c values at last appointment [geometric mean (range) 10.9 (8.4-13.6) vs. 7.4 (5.6-12.5)%, p = 0.01) and those with greater increases in HbA1c over time (+4.1 (3.1) vs. +0.2 (1.9)%, p = 0.009). Of the 33,9 (27%) were lost to follow-up. CONCLUSIONS: At present, T2DM in youth remains a low burden on our services. Patients with this diagnosis, however, have significant problems that present a major challenge to the development of effective management strategies.

Three siblings with self-resolving congenital hyperthyrotropinaemia secondary to thyrotropin receptor blocking antibodies.

Thyrotropin receptor blocking antibodies are a rare cause of hyperthyrotropinaemia and more rarely of congenital hypothyroidism. We report a case of hyperthyrotropinaemia but normal thyroid hormone in the newborn of a mother with hypothyroidism treated with thyroxine. Two older siblings had similar high thyrotropin and normal thyroid function in the newborn period which did not require hormone treatment and resolved spontaneously. Demonstration of thyrotropin receptor antibodies in the child confirmed our diagnosis. Our case was not treated with thyroid replacement hormone and has remained biochemically euthyroid, with thyrotropin levels returning to normal over a period of months.

Ethnic differences in insulin resistance and body composition in United Kingdom adolescents.

CONTEXT: Type 2 diabetes is increasingly recognized in childhood, occurring more frequently in the United Kingdom in South Asians and in girls. South Asian children have been shown to be more insulin resistant than white European children, and girls more insulin resistant than boys. It is not clear how these sex and ethnic differences relate to body composition in childhood. OBJECTIVE: The goal was to evaluate sex and ethnic differences in insulin sensitivity and body composition in healthy adolescents. DESIGN: This was a cross-sectional cohort study. SETTING: This was a community-based study. PARTICIPANTS: One hundred twenty-nine healthy white European and South Asian 14- to 17-yr-old adolescents participated. INTERVENTIONS: Body composition was assessed by anthropometry and dual-energy x-ray absorptiometry, and insulin sensitivity by homeostasis model assessment. MAIN OUTCOME MEASURES: The main outcome measures were body fat percentage and insulin sensitivity. RESULTS: We confirmed that South Asian adolescents were less insulin sensitive than white European adolescents (homeostasis model assessment of insulin sensitivity, 52.4 vs. 58.9%, P < 0.05), with a trend toward lower insulin sensitivity in girls. South Asian adolescents had significantly more body fat than white European adolescents (girls, 30.6 vs. 26.0%, P < 0.005; boys, 20.8 vs. 14.8%, P < 0.001), with more central fat (waist-thigh ratio in girls, 1.36 vs. 1.25, P < 0.001; boys, 1.52 vs. 1.42, P < 0.001). The sex-ethnic differences in insulin sensitivity were no longer seen when body fat was included as a covariate. CONCLUSIONS: Ethnic differences in insulin sensitivity are associated with ethnic differences in body fat. South Asian adolescents are more insulin resistant, with more body fat than white European adolescents, which may contribute to their increased risk of developing type 2 diabetes.